A qualitative survey on factors affecting depression and anxiety in patients with rheumatoid arthritis: a cross-sectional study in Syria

Depression and anxiety often coexist with rheumatoid arthritis (RA) and affect the course of the disease. These mental health conditions can be overlooked or underdiagnosed in people with RA. There is conflicting evidence in previous studies regarding this topic, indicating that further research is necessary to provide a thorough understanding of the relationship between anxiety, depression, and RA. This study aims to determine the factors correlated with depression and anxiety symptoms in RA patients by evaluating disease activity at the same time. This cross-sectional study was conducted at four outpatient rehabilitation centers in four Syrian provinces: Damascus, Homs, Hama, and Latakia. The study included RA patients who attended the RA department of rehabilitation centers from January 1 to June 31, 2023. RA patients who presented at a rheumatology clinic were selected consecutively. RA patients were included in the study in accordance with the ACR/EULAR classification criteria, disease activity was assessed by disease activity score based on the 28-joint count (DAS28), and patients with DAS28 > 2.6 were considered to have active RA. The demographic data, as well as disease duration, educational status, Disease Activity Score with 28-joint counts (DAS28), health assessment questionnaire (HAQ) score, and the hospital anxiety and depression scale (HADS), were the parameters used in the analysis. Two hundred and twelve patients (female, 75%) with a mean age of 49.3 ± 13.1 years and a mean disease duration of 8.3 ± 6.9 years were studied. Depression was diagnosed in 79 (37.3%) patients and anxiety in 36 (16.9%) patients. Patients with depression and/or anxiety had higher HAQ and DAS28 scores compared to other RA patients. Blue-collar workers exhibited a higher prevalence of anxiety, whereas females, housewives, and individuals with lower educational attainment demonstrated a higher prevalence of depression. The current study found high rates of anxiety and depression in RA patients, highlighting the significant burden of these mental health conditions compared to the general population. It is essential for healthcare providers not to overlook the importance of psychiatric evaluations, mental health assessments, and physical examinations of RA patients.


Patients and setting
This cross-sectional study was conducted at four outpatient rehabilitation centers in four Syrian provinces: Damascus, Homs, Hama, and Latakia.The study included RA patients who attended the RA department of rehabilitation centers from January 1 to June 31, 2023.This study included all the patients who met the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria 19 ,while depression and anxiety were diagnosed using the hospital anxiety and depression scale (HADS) 20 , a 14-item questionnaire with seven subscales for anxiety and depression symptoms.Each item is scored on a scale of 0-3, the total score range for each condition is 0-21.Scores of 0-7 indicate no or few anxiety or depression symptoms, 8-10 indicate mild anxiety or depression, and ≥ 11 indicate severe anxiety or depression.The Arabic version of the HADS has been widely used to screen patients with a variety of diseases and has been previously validated for use with the Arabic population 21 .In this study, we defined anxiety and depression as a HADS anxiety score ≥ 8 and a HADS depression score ≥ 8, respectively 21 .
Patient data has been obtained, including age, gender, marital status, employment position, BMI, disease duration, comorbidities, and medication use.The DAS28-ESR was used to assess disease activity, which is based on a 28-joint assessment; 28 tender joint counts (TJC), 28 swollen joint counts (SJC); and the patient global assessment (PtGA) 22 .[R1] The HAQ score was used to evaluate functional status 23 .Pain was evaluated using either the visual analogue scale (VAS), on which items were scored from 0 (no pain) to 100 (maximum pain) 24 .
This study included all patients who met the ACR/EULAR classification criteria, aged between 18 and 85 years and were willing to participate and provide informed consent.Any patient has a history of other autoimmune or inflammatory conditions (e.g.systemic lupus erythematosus, psoriatic arthritis), severe cognitive impairment or neurological disorders that may hinder accurate reporting of depression and anxiety symptoms, pregnant or lactating women, as hormonal changes during these periods can affect mood and anxiety levels, in addition to any patients has a history of psychological disorders (e.g.bipolar disorder, schizophrenia) or had coexisting chronic conditions such as chronic low back pain, chronic non-RA musculoskeletal diseases, cardiovascular disease, cerebrovascular diseases, and gastrointestinal diseases, were excluded from the study.

Statistical analysis
The statistical analyses were performed with the assistance of version 23.0 of the SPSS for Windows software package.The data was evaluated using descriptive statistics such as means, standard deviations, and frequencies.Categorical data was measured using the chi-square test, while continuous variables were computed using Student's t-test or the Mann-Whitney U test.Multivariate logistic regression analyses were used to determine the relationship between clinical and demographic factors and anxiety depression or anxiety among rheumatoid arthritis patients.The results were presented as odds ratios with 95% confidence intervals.A p-value less than 0.05 was considered statistically significant.

Ethics approval and consent to participate
The Ethical Committee approved this study in the Al Baath University Institutional Review Board Consent Letter -IRB 2023168-S and all procedures were conducted under the ethical principles outlined in the 1964 Declaration of Helsinki and its subsequent revisions.Patients were informed of the study's purpose and procedures.In addition, written informed consent to participate in this study was provided by the participants.

Results
This study included a cohort of 212 patients diagnosed with RA.The patients had a mean age (SD) of 49.3 ± 13.1 years (ranging from 20 to 73 years), and the average duration of the disease was 8.3 ± 6.9 years (ranging from 2 to 46 years).Among the participants, 70% were female.The mean DAS28 (SD) was 2.6 ± 1.2, and the mean HAQ score was 1.08 ± 1.2.
Tables 1 and 2 provides an overview of the descriptive statistics for various variables, including age, BMI, disease duration, DAS28, HAQ, and HADS scores, as well as information on gender, marital and working status, education level, comorbidities, and medications utilized.Based on the Arabic validation scores of the hospital anxiety and depression scale (HADS), anxiety symptoms were present in 16.9% of the patients, while depression symptoms were detected in 37.3% of the participants.
Tables 2 comprehensively compare various factors, including gender, marital and employment status, education level, comorbidities, and medication usage, among patients with and without anxiety and depression.The results revealed statistically significant differences in the working status between patients with and without anxiety and depression (p = 0.033, p = 0.042), respectively.Additionally, significant differences were observed in terms of sex and working status between patients with depression and those without depression (p < 0.05).Of particular note, it was found that anxiety levels were considerably higher in individuals employed in blue-collar occupations compared to retired patients.The prevalence of depression was significantly higher in women compared to men.Additionally, it was found to be more prevalent among patients with lower levels of education www.nature.com/scientificreports/(uneducated) compared to those with a high school or university education.Furthermore, housewives had a higher prevalence of depression compared to retired patients.Regarding medication usage, a comparison was made between users of bDMARD and csDMARD.The analysis revealed no statistically significant difference in the levels of anxiety and depression between these two groups of medication users.This information is detailed in Table 2.
Table 3 presents the comparisons of BMI, age, duration of disease, HAQ, and DAS28 scores between different groups.It was observed that patients with both anxiety and depression had significantly higher DAS28 and HAQ scores compared to patients without depression and anxiety (p < 0.05), indicating higher disease activity and worse functional status.

Discussion
RA is a chronic autoimmune disease that primarily affects the joints.It is characterized by inflammation of the synovial lining in multiple joints, leading to joint pain, swelling, stiffness, and progressive joint damage.RA is classified as an inflammatory type of arthritis.RA can also present with extra-articular manifestations, meaning it can affect other organs and systems in the body.These extra-articular manifestations can include symptoms such as depression, fatigue, and sleep disturbance 25,26 .This study aimed to determine the frequency and the factors affecting depression and anxiety in patients with RA.
In this study, depression was determined in 37.3% of the patients, and anxiety in 16.9%.Patients with depression and anxiety had significantly higher DAS28-ESR and HAQ scores than those without depression and anxiety.Depression was determined at a higher rate in females, patients with a low level of education, and housewives, while a university education level was associated with a reduced risk of depression.Anxiety was determined at higher rates in blue-collar workers.Our results are consistent with a study conducted by Altan et al. 27 reported a depression rate of 44% and an anxiety rate of 38% in patients with RA, and a study conducted by Isık et al. 28 that used the HADS-A and HADS-D scales and found anxiety and depression rates of 41.5% and 13.4% in patients with RA, On contract, in a systematic review of 21 studies that included 4,447 RA patients, found a prevalence of depression of 48%among RA patients 29 .
Different rates of depression and anxiety have been recorded in various research, and these disparities have been associated with factors such as study design, scales employed, and a probable relationship with geography and social and economic status 29 .In a study of Brazilian patients with RA, depression was more prevalent among www.nature.com/scientificreports/Brazilians and high disease activity is associated with depression 30 .In another study conducted in Italy among RA patients, depression was detected in 14.3%.and it found a substantial rise in the risk of depression with male sex, a high HAQ score, patient global evaluation, and the use of antidepressants 31 .The results of this study are not consistent with previous studies, where sex, a high HAQ score, age, BMI, and disease duration do not show the risk of depression and anxiety, in return, it found that the work status has a significant increase in the risk of depression and anxiety among RA patients.It is accepted that there is a two-way relationship between RA and depression 20,29 .Depression is seen more in RA patients, and there has been found to be an increased risk of RA development in individuals with depression.There are increased proinflammatory cytokines in depression similar to in RA, and these cytokines are reduced with antidepressant treatment 8 .In patients with severe depressive disorder, the risk of developing RA is increased by 38% compared to the normal population and the risk of RA development has been reported to be reduced in those using antidepressants compared to non-users 32 , some anti-cytokine treatments used in RA have been found to affect depression positively 33 .
In a study by Ng et al. 34 , anxiety and depression were strongly associated with DAS28-ESR.The study also found that depression was significantly lower in patients using etanercept, and these results are consistent with our study where anxiety and depression were associated with DAS28-ESR (p = 0.032, p = 0.021), respectively.
It is necessary to highlight the importance of the impact of depression and anxiety on the management and outcomes of rheumatoid arthritis.Understanding the association between mental health conditions and disease activity can aid in developing comprehensive treatment approaches for individuals with rheumatoid arthritis, wherein a study conducted by Matcham et al. 35 on 18,421 RA patients receiving biological treatment revealed that the response to treatment in the first year was reduced by 20-40% when depression was present at the beginning of the treatment.These results suggest that depression can have a negative impact on the effectiveness of biological treatment in RA patients.In another study by Fragoulis et al. 36 , which involved 848 early RA patients, anxiety was reported to be 19.0%, while depression was 12.2%.The study also identified a relationship between depression and anxiety, disease activity, and poor functional outcomes in patients with early rheumatoid arthritis.
A low socioeconomic status, female sex, young age, and functional limitations have been reported to be factors associated with depression in RA patients 34 .Depression is generally associated with the severe form of RA 35 .In a meta-analysis, Zhang et al. 33 determined higher disease activity and lower quality of life in RA patients with depression compared to those without depression 37 .In addition, Watad et al. 38 found higher levels of anxiety in RA patients compared to a control group, and low socioeconomic status was reported to be an independent factor associated with anxiety.In another study, low socioeconomic status and high DAS28 scores were determined to be associated with anxiety 36 .Our results are in line with previous studies which showed that individuals diagnosed www.nature.com/scientificreports/with RA who also experienced depression and anxiety displayed higher levels of disease activity and lower quality of life compared to RA patients without, but no difference was determined concerning pain.In our study, when bDMARD and csDMARD users were compared, no statistically significant difference was found in terms of anxiety and depression.However, we noticed a substantial variation in patients' DAS28 and HAQ scores and the presence of depression and anxiety.Similarly, in another study, bDMARDs and csD-MARDs were not superior in depression 36 .More research is needed to investigate the impact of bDMARDs on anxiety and depression.A study of 464 RA patients found that depression was associated with the global health score, while anxiety was associated with being married and having a functional disability 39 .In another study, it was reported that the presence of anxiety and depression in patients with RA can cause suicide and diminished quality of life and can worsen the prognosis of RA 40 .The study had some limitations, including a relatively small sample size, and a cross-sectional design.Additionally, there was no control group in the study, and the patients' social and economic situation was not investigated.Since in just four rehabilitation centers, the results may not be generalizable to all RA patients.

Conclusion
Anxiety and depression are highly prevalent among (RA) patients, and it is important to consider that this may impact the patients' response to treatment, prognosis, and even mortality.Therefore, it is recommended to collaborate with the psychiatry department in managing these cases.

Table 3 .
Comparison of demographic and clinical characteristics between patients with and without anxiety and depression.Statistical significance was calculated using the Mann-Whitney U test.DAS28 disease activity score with 28-joint counts, TJC tender joint count, SJC swollen joint count, PtGA patient global assessment, HAQ health assessment questionnaire, VAS visual analog scales.

Table 4 .
Multivariate analysis for demographic and clinical factors associated with anxiety and depression in patients with rheumatoid arthritis.OR (95% CI) odds ratios (95% confidence intervals).DAS28 disease activity score with 28-joint counts, HAQ health assessment questionnaire.